Huntington's disease (HD) is a genetic brain disease that reveals itself in mid-life with slowly progressive dysfunction of motor, cognitive and emotional systems due to cell death in the striatum and related circuitry disruption. The genetic mutation consists of an expansion in the number of polyglutamine (CAG) repeats and the number of repeats is associated with HD onset, accounting for at least 50% of the variability in age. Efforts are underway to better understand the pathogenesis of HD and to derive more discrete estimates of its onset. In another study we are evaluating persons who have the gene mutation for HD, but do not yet demonstrate the clinical signs of illness (hereafter referred to pre-HD). Structural MRI and comprehensive neuropsychological and psychiatric assessments are being conducted to detect subtle disease before traditional motor symptoms appear. Preliminary work from our group suggests that a combined use of imaging and cognitive challenge tasks allow detection of early dysfunction. Using cognitive-activated magnetic resonance imaging (or functional MRI) we hope to increase our understanding of normal basal ganglia function and allow us to monitor and characterize the development of basal ganglia pathology in HD. Sixty pre-HD and thirty healthy control subjects will be enrolled and examined longitudinally at two time points separated by a 30-month interval. The MRI sessions will include anatomical scans to assess brain structure and functional MRI (fMRI) of four cognitive tasks sensitive to basal ganglia function: time discrimination, conceptual reasoning, motor timing, and response inhibition. The specific aims are to examine the sensitivity of fMRI in identifying neural dysfunction in pre-HD participants and to determine the association between DMA-based estimations of disease onset and indices of brain dysfunction over time. The proposed project will advance our understanding of the neurobiology of HD as well as the role of corticostriatal circuitry in mediating cognitive functions. [unreadable] [unreadable] [unreadable]